On May 21, I was contacted by Jeff Macdonald, communications director at Acorda Therapeutics, Inc., a company which is developing treatments for multiple sclerosis and other neurological disorders. They have a product for which they will be seeking FDA approval early next year. Jeff thought that you and I would be interested in learning about milestones in their clinical development. We even talked on the phone just after Memorial Day to discuss Fampridine-SR.
On June 2, Acorda released the following press release regarding positive results from the second of two Phase III trials of a drug called Fampridine-SR in the treatment of MS. As any MSer with very slight obsessive-compulsive tendencies, I felt compelled to do some research before blindly presenting you with Acorda's information. I don't know about you, but I like to know more than what is summarized in a press release. Included is personal commentary, not in italics.
Much of what I found is presented in these recent posts:
- What is 4-Aminopyridine?
- 4-AP, Fampridine-SR, and Spinal Cord Injury
- 4-AP, Fampridine-SR, and Multiple Sclerosis
- The Bioentrepreneur and Fampridine
Hawthorne, NY, June 2, 2008 - Acorda Therapeutics, Inc. (NASDAQ: ACOR) today announced positive results from its second Phase 3 clinical trial of Fampridine-SR (MS-F204) on walking ability in people with multiple sclerosis (MS). A significantly greater proportion of people taking Fampridine-SR in the trial had a consistent improvement in walking speed compared to people taking placebo (42.9% vs. 9.3%), as measured by the Timed 25-Foot Walk (p less than 0.001). Consistent improvement in walking speed was the primary endpoint of the study as outlined in the Special Protocol Assessment (SPA) with the U.S. Food and Drug Administration (FDA).The number of patients taking Fampridine-SR in this trial was 120, according to the study design description below. But 42.9% of 120 patients total 51.5 patients. Perhaps it is 42.9% of 119 patients, being 51 patients, who became responders in this trial with consistent improvement in walking speed.
“With the success of this trial, we have achieved a critical milestone for Fampridine-SR. We have now completed two successful Phase 3 trials demonstrating improved walking ability in people with MS,” said Ron Cohen, M.D., President and CEO of Acorda Therapeutics. “We believe that, subject to FDA review, the results of our two Phase 3 trials are adequate to support an NDA. We expect to submit this application in the first quarter of 2009 and plan to request priority review.”I don't know too much about the FDA approval process, but I doubt that Fampridine-SR will hit the market before 2010. According to a Reuters article, Fampridine-SR "might cost between $5000 to $10,000 per year." When I spoke with Jeff Macdonald in May, he could not offer any guidance on the expected cost. He said that they (Acorda) were focused simply on getting FDA approval right now. I also asked him about any plans for a patient assistance program. He answered that with approval they expect that insurance will reimburse the cost. Arghh! Why is that always the cop-out answer when the cost of medication is called into question? I have insurance and there's no way it would cover this drug, just as it doesn't cover the cost of Copaxone.
The study’s only prospectively defined secondary outcome measure, leg strength, showed a statistically significant increase in the Fampridine-SR Timed Walk responders compared to placebo (p = 0.028). There was a small improvement in leg strength for Fampridine-SR Timed Walk non-responders compared to placebo that was not statistically significant.Between 1997 and 2002, Dr. Goodman was instrumental in conducting a number of studies which focused on how best to measure impairment and changes in impairment levels. A study published in 2002 concluded that a 20% change in qualitative functional measurement can be considered a reliable threshold to indicate true change in function for an individual. What this means is that variation in walking speed of the Timed 25-Foot Walk up to 20% could be considered within acceptable fluctuations of ability without indicating a true change in function. So the average increase in walking speed of 24.7% does not impress me as greatly as Acorda would probably hope.
Additional measures in this study were consistent with the results of the first Phase 3 Fampridine-SR trial. The average increase in walking speed over eight weeks of treatment compared to baseline was 24.7 percent for the Fampridine-SR Timed Walk responders compared to 7.7 percent for the placebo group. The 12-Item Walking Scale (MSWS-12), a self-rated assessment of walking disability, was improved in Timed Walk responders compared to nonresponders. Also, an increased response rate on the Timed 25-Foot Walk was seen across all four types of MS. The Company intends to present comprehensive data from this trial at an upcoming medical meeting.
“Difficulties with walking are among the most pervasive and debilitating problems faced by people with MS. Walking disability affects their ability to accomplish daily tasks and limits their independence,” said Andrew Goodman, M.D., Director of the Multiple Sclerosis Center at the University of Rochester. “Because there are currently no therapies indicated to improve walking impairment in MS, clinicians are limited in their ability to address this aspect of the disease. The results of this study indicate that Fampridine-SR could represent an important new way to treat people with MS.”I do not disagree with Dr. Goodman's characterization that difficulties in walking do impact a patient's ability to accomplish tasks with ease. In fact, difficulties with spastic leg muscles causes me trouble. However, I find the statement regarding "no therapies indicated to improve walking impairment in MS" to be promotional in nature. For me, a prescription of the muscle relaxant, Baclofen, has tremendously improved my ease of walking and costs much less than Fampridne-SR will.
Study DesignSo if the estimated cost of MS is greater than $47,000 per patient per year, why not go ahead and increase the cost 21% by adding yet another drug into the mix? However I believe the NMSS estimate is inaccurate. Here's why I believe that to be the case based on my experience and research.
The double-blind, placebo-controlled trial was designed to evaluate the safety and efficacy of Fampridine-SR in improving walking ability in people with MS. The primary endpoint of the study was response on the Timed 25-Foot Walk. A Fampridine-SR Timed Walk responder was defined as a study participant whose walking speed was faster at a majority of the four on-drug visits than any speed measured during the five off-drug visits. The trial, which enrolled 240 individuals at 39 MS centers in the United States and Canada, recruited patients between 18 and 70 years old with a definite diagnosis of MS and some degree of walking disability. Subjects were randomized to treatment with Fampridine-SR (n=120), at a dose of 10mg twice a day, or placebo (n=119), and the study was open to people with all four major types of MS: primary-progressive, secondary-progressive, relapsing-remitting and progressive-relapsing. Participants were permitted to remain on a stable regimen of their current medications, including immunomodulators.
In this study, adverse events were generally mild to moderate and largely consistent with the safety profile observed in previous studies of Fampridine-SR in people with MS. The most common adverse events reported in the Fampridine-SR treatment group compared to the placebo group included: urinary tract infection (17.5% vs. 8.4%), falls (11.7% vs. 16.8%), insomnia (10.0% vs. 1.7%), headache (9.2% vs. 0.8%), asthenia (8.3% vs. 4.2%), dizziness (8.3% vs. 0.8%), nausea (8.3% vs. 0.8%), back pain (5.8% vs. 2.5%), balance disorder (5.8% vs. 1.7%), upper respiratory tract infection (5.8% vs. 6.7%), arthralgia (5.0% vs. 4.2%), nasopharyngitis (5.0% vs. 4.2%) and paraesthesia (5.0% vs. 1.7%).
There were three serious adverse events (SAEs) that led to discontinuation: two in the placebo group and one in the Fampridine-SR group. In the placebo group, one participant experienced a possible complex partial seizure and another experienced a combination of chest tightness and gastric reflux. Both of these events were judged by investigators, who were blinded at the time, to be possibly related to treatment. In the Fampridine-SR group, one participant had a patellar fracture, which was judged not to be treatment related. In addition, one participant treated with Fampridine-SR experienced an episode of syncope (fainting) one day after completing the treatment phase of the study. This was judged to be possibly related to treatment, but the participant was not discontinued from the trial. Follow-up assessment by the clinical investigators determined that these SAEs resolved completely with no residual effects. No deaths occurred during the study.
As of June 2, 2008, the total exposure in our MS studies to Fampridine-SR at 10mg twice a day, including both double-blind and open-label studies, is approximately 1,100 patient years. The incidence of seizures in these studies at the 10mg dose has been within the rates reported for placebo-treated groups in long-term controlled studies of immunomodulator drugs in MS patients. These rates have ranged up to two percent of patients in a two-year study, or one seizure per 100 patient years. The overall incidence of seizure appears to be dose-related.
Multiple sclerosis is a chronic, usually progressive disease in which the immune system attacks and degrades the function of nerve fibers in the brain and spinal cord. Over 400,000 Americans have MS, and someone is newly diagnosed with MS every hour in the United States. Most are between the ages of 20 and 50, and women are affected two to three times as much as men. Worldwide, MS may affect 2.5 million individuals.
According to the National Multiple Sclerosis Society (NMSS), the direct costs of medical care for MS patients in the United States exceed $6 billion annually. Additionally, a NMSS analysis estimated the total cost of MS, including medical and non-medical care, production losses, and informal care, at more than $47,000 per U.S. patient per year. Complications from MS may make it harder for people to work and may interfere with their ability to perform common daily activities.
- $25,000 Copaxone
- $01,360 Gabapentin
- $00,840 Baclofen
- $00,184 Sertraline
- $03,540 Provigil
- $00,088 Annual Neurological Exam ($237 billed)
- $03,500 Insurance Premiums
- $06,000 Cost of relapse-related medical care ($10,500 billed)
- $02,000 Loss of earnings during relapse
- $10,000 Loss of earnings by cutting back hours due to fatigue
- $00,500 Cost of Membership to County RecCenter with Pool
- $00,500 Cost of Yoga Classes at County RecCenter
Being disgusted with the above - Priceless
For most people with MS, the disease slowly progresses with a series of unpredictable flare-ups, also called relapses. But for some, the progression of the disease is rapid. Each relapse tends to lead to increasing disabilities such as walking impairment, muscle weakness or speech or vision impairments. Approximately 85 percent of people with MS experience some form of walking impairment. Within 15 years of an MS diagnosis, 50 percent of patients often require assistance walking and, in later stages, up to a third of patients are unable to walk.
Fampridine-SR is a sustained-release tablet formulation of the investigational drug fampridine (4-aminopyridine or 4-AP). In laboratory studies, fampridine has been found to improve impulse conduction in nerve fibers in which the insulating layer, called myelin, has been damaged. Fampridine-SR is being developed by Acorda Therapeutics and manufactured by Elan Corporation plc.
Fampridine-SR and MS
A nerve cell has one extension, called an axon, which it uses to communicate via electrical signals to other nerve cells. All but the smallest axons have a special covering of a fatty substance called myelin that acts as insulation to preserve and speed these nerve signals, much like the insulating cover of an electrical cord helps preserve the transmission of electricity.
In MS, the myelin becomes damaged and the axon cannot effectively transmit electrical impulses. Specifically, the damaged myelin exposes channels in the membrane of the axon, which allow potassium ions to leak from the axon, dissipating the electrical current. In published studies, fampridine has been shown to block these exposed channels and help the electrical signals to pass through areas of damage.
Loss of Mobility Found to Impact Quality of Life and Emotional and Financial Health of Most People Living with Multiple Sclerosis
Two new complementary surveys provide groundbreaking data on the impact of walking impairment on people living with multiple sclerosis, revealing challenges related to quality of life, family relationships, independence, work, financial security and other areas.
"Among the many important conclusions we can draw from these studies is that they indicate we must educate more people with MS and care partners about the impact of mobility loss and the options now available to address mobility challenges," said Dr. Nicholas LaRocca, vice president, health care delivery and policy research, National MS Society.
"Many people do not realize the extent to which symptoms such as fatigue can affect people living with MS. Physical fatigue is a very common symptom of MS that can also affect mobility and balance. This study clearly demonstrates that it is essential to assess the impact of multiple symptoms in MS in order to develop effective educational programs and treatment strategies," observed Dr. LaRocca."These surveys provide important new insights about how walking disability affects the quality of life of people with MS, their families and other care partners. Examining walking disability from different perspectives can help provide a better understanding of its prevalence and impact. These findings, coupled with previous research on aspects of walking impairment such as the use of assistive devices, highlight the need to continue to develop new treatment options," said Andrew Blight, Ph.D., chief scientific officer of Acorda Therapeutics.
"As someone who has lived with MS for over two decades now, I see that people with MS are living fuller and more active lives than ever before, but we clearly have a long way to go. For me, MS and especially mobility issues have had a direct impact on my ability to work and the cost of my care. These surveys shed new light on the challenges that thousands of us with MS are experiencing every day," said Mimi Mosher, a patient advocate from Mechanicsville, VA, and a person living with MS who uses both a scooter and a wheelchair.
Finally, check out the non-branded outreach program which Acorda initiated this spring to coincide with the many MS Walks around the country.
I write because I can. I research because I must. I share for me and you. I hope for a cure as much as others do. I expect some MSers will derive benefit from Fampridine-SR and others will not. I know that I will not be able to afford it, even with the insurance I have now. I sincerely hope that it might give folks like Diane in Seattle a new level of functioning. But the more this drug is hyped, the less faith I have that it...well, I simply become less enthusiastic. Just my personal opinion.
So there it is folks. These five posts regarding 4-AP, Fampridine and Acorda Therapeutics are all I've got. I trust that you've found them informative.